SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy

Abstract

Background: SARS-CoV-2 enters cells by binding of its spike protein to angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have been reported to increase ACE2 expression in animal models, and worse outcomes are reported in patients with co-morbidities commonly treated with these agents, leading to controversy during the COVID-19 pandemic over whether these drugs might be helpful or harmful.

Methods: Animal, in vitro and clinical data relevant to the biology of the renin-angiotensin system (RAS), its interaction with the kallikrein-kinin system (KKS) and SARS-CoV-2, and clinical studies were reviewed.

Findings and interpretation: SARS-CoV-2 hijacks ACE2to invade and damage cells, downregulating ACE2, reducing its protective effects and exacerbating injurious Ang II effects. However, retrospective observational studies do not show higher risk of infection with ACEI or ARB use. Nevertheless, study of the RAS and KKS in the setting of coronaviral infection may yield therapeutic targets.

Keywords: ACE inhibitors; ACE2; ARBs; COVID-19; Kallikrein-kinin system; Renin-angiotensin system; SARS-CoV-2.

Fig. 1

ACE and ACE 2 pathways. Renin from the kidneys converts angiotensinogen to Ang I. ACE, and to a lesser extent secreted proteases, such as chymase, catalyzes the conversion of Ang I to Ang II. Ang II binds to the angiotensin II receptor AT1R, leading to vasoconstriction and cellular injury pathways. ACEIs inhibit the conversion of Ang I to Ang II, reducing Ang II production, while ARBs block the Ang II receptor, AT1R. The ACE-Ang II-AT1R pathway is balanced by ACE2, which degrades Ang II and Ang I to produce Ang 1–7 and Ang I to Ang 1–9. Ang1–7 and Ang 1–9 pathways exert protective effects via the receptors Mas1 and AT2R, respectively. Downregulation of ACE2 is associated with an increase in Ang II and activation of the Ang II / AT1R pathway. Upregulation of ACE2 degrades Ang I, limiting the substrate for ACE, degrades Ang II, limiting its adverse effects, and generates Ang 1–7 and Ang 1–9, leading to protective effects. ACE2 is shed from the cell surface by the action of ADAM 17, which is dispensable, but which releases a soluble active form of ACE2 and reduces membrane-bound ACE2. Ang I - angiotensin I. Ang II - angiotensin II. Ang 1–7 - angiotensin 1–7. ACE - angiotensin converting enzyme. ACE 2 - angiotensin converting enzyme 2. AT1 R - angiotensin 1 receptor. AT2 R - angiotensin 2 receptor. Mas1 R - mitochondrial assembly receptor. ACEI - angiotensin converting enzyme inhibitor. ARB - angiotensin 1 receptor blocker.

Fig. 2

Interactions between the renin-angiotensin system and kallikrein-kinin pathways. Factor XII (FXII) autoactivates and then cleaves plasma prekallikrein to activate plasma kallikrein. FXII and plasma kallikrein continue to activate each other, augmenting their activity. Plasma kallikrein cleaves high molecular weight (HMW) kininogen to form bradykinin (BK). The renin-angiotensin system angiotensin converting enzyme (ACE) or kininase enzymes are involved in kinin metabolism. BK is hydrolyzed by ACE into des-Arg⁹-BK and inactive products. ACE2 breaks down des-Arg9-BK into inactive peptides. BK and des-Arg9-BK interact with two G-protein-coupled bradykinin receptors (B1R and B2R) at the cellular membrane to cause inflammation with release of IL-1, IL-2, IL-6, and IL-8 cytokines; vasodilation via the nitric oxide synthase (NOS), nitric oxide (NO) and cyclic GMP pathway; contraction of non-vascular smooth muscle; increased vascular permeability; and fluid extravasation. Plasma kallikrein inhibitors and B2 receptor antagonists (e.g. icatibant) are two categories of medications used to treat hereditary angioedema, a rare genetic condition.

Fig. 3

SARS-CoV-2 interaction with ACE 2 and TMPRSS 2. The spike protein around SARS-CoV-2 binds to its receptor, ACE2, driving fusion of viral and host cell membranes. Viral entry is also dependent on spike protein priming at its S1/S2 cleavage site (e.g. by furin) and then at its S2′ site by TMPRSS2, a process inhibited by camostat mesilate and serine protease / furin inhibition. Although SARS-CoV-2 fusion is thought to occur in the endosomes of target cells, the requirement of cathepsins B and L for optimal membrane fusion efficiency in vivo remains unclear. Chloroquine increases the pH of lysosomes and is thought to inhibit the activity of proteases that promote membrane fusion and viral release into the cell. Ang I - angiotensin I. Ang II - angiotensin II. Ang 1–7 - angiotensin 1–7. ACE - angiotensin converting enzyme. ACE 2 - angiotensin converting enzyme 2. AT1 R - angiotensin 1 receptor. Mas1 R - mitochondrial assembly receptor. ACEI - angiotensin converting enzyme inhibitor. ARB - angiotensin 1 receptor blocker. TMPRSS2 - transmembrane protein serine protease 2.

Fig. 4

Gene expression by tissue of potential genes encoding proteins that may interact with SARS-CoV from GTEx. The lung and intestines express high levels of ACE2 and TMPRSS2, whereas the heart left ventricle expresses ACE2 at high levels, but TMPRSS2 at low levels. Brain tissues show low level expression of ACE2 and TMPRSS2. CTSB and CTSL (encoding cathepsins B and L, respectively), ADAM17, ADAM10, and FURIN show expression in all tissues shown. Obtained from the Genotype-Tissue Expression (GTEx) Portal, accessed on 04/06/2020 and 05/06/2020.